Smoking is the single largest preventable cause of disease and premature death. It is a prime factor in heart disease, stroke and chronic lung disease. Long-term smoking has been highly correlated with cancer of the lungs, larynx, esophagus, mouth, and bladder, and also likely contributes to cancer of the cervix, pancreas, and kidneys. In the United States, an estimated 25.1 million men (23.4 percent) and 20.9 million women (18.5 percent) are smokers (National Health Interview Survey, 2004). Smoking related-diseases account for one in 10 adult deaths globally, which translates to four million deaths annually. By 2030, if current trends continue, diseases or complications related to smoking will kill one in six people. Tobacco smoke contains the psychoactive stimulant nicotine, which has been demonstrated to sustain addictive tobacco use, which in turn leads to loss of control over smoking behavior. Nicotine acts on a4B2, a7 and a6-containing neuronal nicotinic receptors (nAChRs) to facilitate neurotransmitter release (dopamine and others), producing pleasure, stimulation, and mood modulation. With repeated exposure to nicotine, tolerance and sensitization occur to many of the effects of nicotine. When a smoker stops smoking, a nicotine withdrawal syndrome ensues, characterized by irritability, anxiety, increased eating, dysphoria, and hedonic dysregulation, among other symptoms. Pharmacotherapy to aid smoking cessation should ideally reduce nicotine withdrawal symptoms and block the reinforcing effects of nicotine obtained from smoking without causing excessive adverse effects. Smoking cessation substantially reduces the risk of cardiovascular disease in the prevention of primary and secondary cardiovascular events. Until recently, first-line therapies for smokers who wanted to quit included nicotine replacement therapy and bupropion. Novel treatments currently in clinical trials include nicotine vaccines. In 2006, Chantix (varenicline), a novel treatment was approved by the FDA for smoking cessation. Varenicline, promoted as an a4P2 nicotinic acetylcholine receptor partial agonist, is the first nAChR-based drug therapy to have reached the market, and as such has validated the nAChR mechanism. As a smoking cessation therapeutic, varenicline increases abstinence rates and decreases craving and withdrawal to a greater extent than nicotine replacement therapy or bupropion (Fagerstrom and Hughes 2008). However, there is much potential for improvement over varenicline, as its dosing regimen is not straightforward (with regard to the initial dose titration and twice daily dosing to reduce the occurrence of nausea)(Chantix Prescribing Information. Precautions: General.)! and compliance is limited by a narrow margin of tolerance. Nausea and vomiting are the most common complaints about varenicline in the clinic and these side effects are thought to be mediated by the interaction of varenicline with the 5HT{3} receptor and the a3P4 nicotinic receptor. The Institute of Safe Medication Practices (2008) recently published a report stating that varenicline had more FDA adverse event reports per quarter in absolute numbers than any other marketed drug. The adverse events included accidents, visual disturbances, heart rhythm disturbances, hyperglycemia and hostility/aggression. However, the report did not take into account the large number of people taking varenicline (estimated to be 4 million) and the degree of concomitant medication and pre-existing medical conditions(Hays, 2008). In addition, Pfizer has added a warning to varenicline's label to include depression, suicidal ideation and other behavioral changes. Given that anxiety/depression and behavioral changes are related to smoking cessation and there is a large degree of comorbidity between smoking and mental illness, as well as concomitant abuse of nicotine with other psychoactive drugs (e.g. ethanol), it is difficult to determine whether these behavioral effects are due to varenicline, underlying psychiatric issues or substance abuse issues, or the act of smoking cessation itself.